People living in areas where Plasmodium falciparum (Pf) and P. vivax (Pv) are endemic develop naturally acquired immunity to malaria blood stage infection and illness after repeated exposures to the parasite through childhood and adolescence. The rate at which this immunity develops is variable due to local differences in the intensity and temporal stability of transmission. A global effort is now underway to control and ultimately eliminate Pf and Pv through the use of vector interventions such as insecticidal bed nets. The goal of research proposed here is to identify novel and robust antibody assays to guide this effort. Probing a protein microarray containing 2,320 Pf proteins with sera collected from Pf-exposed Malian children and adults indicated that long-lived antibody responses against hundreds of antigens are acquired after years of repeated Pf infections and antibodies associated with protection were identified against 49 specific Pf antigens. Here we aim to extend these findings with a worldwide sero-epidemiological analysis. This multi-ICEMR project will probe specimens from cross sectional and longitudinal studies in 5 regions around the world which differ in malaria transmission intensity and in Plasmodium species exposure. The array will contain 800 antigens from Pf and Pv, and sera from the studies will be probed annually to determine the effect of vector control and chemoprevention on the development and decline of the serological response. This study will better our understanding of how naturally acquired immunity develops as a function of age and seasonal mosquito exposure. The data may also lead to the discovery of antibody biomarkers associated with parasite exposure and with protection from malarial disease.